Abstract
We previously reported that mouse bone marrow-derived macrophages (BMDMs) that had been co-cultured with platelets exhibited lower susceptibility to bacterial lipopolysaccharide (LPS) and produced lower levels of nitric oxide (NO) and inflammatory cytokines including TNF-α and IL-6. The suppression of macrophage responses was mediated, at least in part, by platelet supernatant. In the present study, we assessed phenotypic changes of BMDMs induced by incubation with the supernatant from thrombin-activated platelets (PLT-sup) and found that BMDMs cultured with PLT-sup (PLT-BMDMs) expressed a lower level of inducible NO synthase (iNOS) and a higher level of arginase-1, both of which are involved in the L-arginine metabolism, upon stimulation with LPS or zymosan. We also examined possible modulation of the NF-κB signaling pathway and observed suppression of IκBα phosphorylation and a decrease of NF-κB p65 expression in LPS-stimulated PLT-BMDMs. These results suggest that PLT-sup suppresses inflammatory responses of BMDMs via negative regulation of NF-κB signaling leading to lowered expression of iNOS and enhanced L-arginine catabolism by arginase-1.
Highlights
Bacterial lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, stimulates macrophages to produce various inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6 [1,2,3]
We first conducted a time-course experiment of the effect of thrombin-stimulated platelet supernatant (PLT-sup) on the LPS-induced nitric oxide (NO) production by macrophages
These results suggest that phenotypic changes of bone marrow-derived macrophages (BMDMs) may take place to attenuate their susceptibility to LPS in the presence of soluble factors derived from activated platelets
Summary
Bacterial lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, stimulates macrophages to produce various inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6 [1,2,3] In addition to these cytokines, nitric oxide (NO) produced by activated macrophages plays important roles in the pathogenesis of inflammation related to bacterial infection [4,5,6,7]. The suppression of macrophage responses by platelets did not necessarily require the direct cell—cell contact between macrophages and platelets, but appeared to be mediated by soluble factors secreted from platelets upon stimulation with thrombin or other stimulants These observations provided a cellular basis for the results of an earlier in vivo study showing that thrombocytopenia increased mortality and aggravated organ failure in LPS-induced endotoxemia [9] and supported the notion that platelets play critical roles in the modulation of inflammatory responses
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